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  • Print publication year: 2013
  • Online publication date: November 2013

Chapter 3 - Genome-wide association study (GWAS) approaches to sleep phenotypes

from Section 1 - Generalprinciples of genetics and genomics
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The Genetic Basis of Sleep and Sleep Disorders
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1. Geyer H. Ueber den Schlaf von Zwillingen. Z Indukt Abstamm Verebungsl. 1937;78:524–27.
2. Redline S, Tishler PV. The genetics of sleep apnea. Sleep Med Rev. 2000;4(6):583–602.
3. Lowrey PL, Takahashi JS. Genetics of circadian rhythms in mammalian model organisms. Adv Genet. 2011;74:175–230.
4. Kerkhof GA, Van Dongen HP. Morning-type and evening-type individuals differ in the phase position of their endogenous circadian oscillator. Neurosci Lett. 1996;218(3):153–56.
5. Paine SJ, Gander PH, Travier N. The epidemiology of morningness/eveningness: influence of age, gender, ethnicity, and socioeconomic factors in adults (30–49 years). J Biol Rhythms. 2006;21(1):68–76.
6. Levandovski R, Dantas G, Fernandes LC, et al. Depression scores associate with chronotype and social jetlag in a rural population. Chronobiol Int. 2011;28(9):771–78.
7. Saksvik IB, Bjorvatn B, Hetland H, et al. Individual differences in tolerance to shift work – a systematic review. Sleep Med Rev. 2011;15(4):221–35.
8. Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet. 2011;378(9785):31–40.
9. Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness–eveningness in human circadian rhythms. Int J Chronobiol. 1976;4(2):97–110.
10. Hur Y-M, Bouchard TJ, Lykken DT. Genetic and environmental influence on morningness–eveningness. Person Individ Differ. 1998;25(5):917–25.
11. Vink JM, Groot AS, Kerkhof GA, et al. Genetic analysis of morningness and eveningness. Chronobiol Int. 2001;18(5):809–22.
12. Klei L, Reitz P, Miller M, et al. Heritability of morningness–eveningness and self-report sleep measures in a family-based sample of 521 Hutterites. Chronobiol Int. 2005;22(6):1041–54.
13. Aguiar GF, da Silva HP, Marques N. Patterns of daily allocation of sleep periods: a case study in an Amazonian riverine community. Chronobiologia. 1991;18(1):9–19.
14. Jones CR, Campbell SS, Zone SE, et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med. 1999;5(9):1062–65.
15. He Y, Jones CR, Fujiki N, et al. The transcriptional repressor DEC2 regulates sleep length in mammals. Science. 2009;325(5942):866–70.
16. Xu Y, Padiath QS, Shapiro RE, et al. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature. 2005;434(7033):640–44.
17. Katzenberg D, Young T, Finn L, et al. A CLOCK polymorphism associated with human diurnal preference. Sleep. 1998;21(6):569–76.
18. Mishima K, Tozawa T, Satoh K, et al. The 3111T/C polymorphism of hClock is associated with evening preference and delayed sleep timing in a Japanese population sample. Am J Med Genet B Neuropsychiatr Genet. 2005;133B(1):101–04.
19. Robilliard DL, Archer SN, Arendt J, et al. The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects. J Sleep Res. 2002;11(4):305–12.
20. Iwase T, Kajimura N, Uchiyama M, et al. Mutation screening of the human Clock gene in circadian rhythm sleep disorders. Psychiatry Res. 2002;109(2):121–28.
21. Pedrazzoli M, Louzada FM, Pereira DS, et al. Clock polymorphisms and circadian rhythms phenotypes in a sample of the Brazilian population. Chronobiol Int. 2007;24(1):1–8.
22. Archer SN, Carpen JD, Gibson M, et al. Polymorphism in the PER3 promoter associates with diurnal preference and delayed sleep phase disorder. Sleep. 2010;33(5):695–701.
23. Ebisawa T, Uchiyama M, Kajimura N, et al. Association of structural polymorphisms in the human Period3 gene with delayed sleep phase syndrome. EMBO Rep. 2001;2(4):342–46.
24. Pereira DS, Tufik S, Louzada FM, et al. Association of the length polymorphism in the human Per3 gene with the delayed sleep-phase syndrome: does latitude have an influence upon it? Sleep. 2005;28(1):29–32.
25. Jones KH, Ellis J, von Schantz M, et al. Age-related change in the association between a polymorphism in the PER3 gene and preferred timing of sleep and waking activities. J Sleep Res. 2007;16(1):12–16.
26. Osland TM, Bjorvatn BR, Steen VM, et al. Association study of a variable-number tandem repeat polymorphism in the clock gene PERIOD3 and chronotype in Norwegian university students. Chronobiol Int. 2011;28(9):764–70.
27. Carpen JD, von Schantz M, Smits M, et al. A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans. J Hum Genet. 2006;51(12):1122–25.
28. Carpen JD, Archer SN, Skene DJ, et al. A single-nucleotide polymorphism in the 5ʹ-untranslated region of the hPER2 gene is associated with diurnal preference. J Sleep Res. 2005;14(3):293–97.
29. Archer SN, Robilliard DL, Skene DJ, et al. A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep. 2003;26(4):413–15.
30. Steemers FJ, Chang W, Lee G, et al. Whole-genome genotyping with the single-base extension assay. Nat Meth. 2006;3(1):31–33.
31. McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008;9(5):356–69.
32. Allebrandt KV, Teder-Laving M, Akyol M, et al. CLOCK gene variants associate with sleep duration in two independent populations. Biol Psychiatry. 2010;67(11):1040–47.
33. Allebrandt KV, Amin N, Muller-Myhsok B, et al. A K(ATP) channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila. Mol Psychiatry. 2013;18(1):122–32.
34. NHANES 2001–2002 Respiratory Health and Disease Questionnaire. Accessed 14 September 2005.
35. Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res. 2002;53(1):547–54.
36. Ekbom K, Ulfberg J. Restless legs syndrome. J Intern Med. 2009;266(5):419–31.
37. Desautels A, Turecki G, Montplaisir J, et al. Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am J Hum genetics. 2001;69(6):1266–70.
38. Bonati MT, Ferini-Strambi L, Aridon P, et al. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain. 2003;126(Pt 6):1485–92.
39. Chen S, Ondo WG, Rao S, et al. Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genetics. 2004;74(5):876–85.
40. Pichler I, Marroni F, Volpato CB, et al. Linkage analysis identifies a novel locus for restless legs syndrome on chromosome 2q in a South Tyrolean population isolate. Am J Hum Genetics. 2006;79(4):716–23.
41. Levchenko A, Provost S, Montplaisir JY, et al. A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13. Neurology. 2006;67(5):900–01.
42. Kemlink D, Plazzi G, Vetrugno R, et al. Suggestive evidence for linkage for restless legs syndrome on chromosome 19p13. Neurogenetics. 2008;9(2):75–82.
43. Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genetics. 2007;39(8):1000–06.
44. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007;357(7):639–47.
45. Mercader N, Leonardo E, Azpiazu N, et al. Conserved regulation of proximodistal limb axis development by Meis1/Hth. Nature. 1999;402(6760):425–29.
46. Mizuhara E, Nakatani T, Minaki Y, et al. Corl1, a novel neuronal lineage-specific transcriptional corepressor for the homeodomain transcription factor Lbx1. J Biol Chem. 2005;280(5):3645–55.
47. Yuan SH, Qiu Z, Ghosh A. TOX3 regulates calcium-dependent transcription in neurons. Proc Natl Acad Sci USA. 2009;106(8):2909–14.
48. Winkelmann J, Czamara D, Schormair B, et al. Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLoS Genetics. 2011;7(7):e1002171.
49. Liebetanz KM, Winkelmann J, Trenkwalder C, et al. RLS3: fine-mapping of an autosomal dominant locus in a family with intrafamilial heterogeneity. Neurology. 2006;67(2):320–01.
50. Kemlink D, Polo O, Montagna P, et al. Family-based association study of the restless legs syndrome loci 2 and 3 in a European population. Mov Disord. 2007;22(2):207–12.
51. Lohmann-Hedrich K, Neumann A, Kleensang A, et al. Evidence for linkage of restless legs syndrome to chromosome 9p: are there two distinct loci? Neurology. 2008;70(9):686–94.
52. Yoss RE, Daly DD. Criteria for the diagnosis of the narcoleptic syndrome. Proc Staff Meet Mayo Clin. 1957;32(12):320–28.
53. Mignot E. Sleep, sleep disorders and hypocretin (orexin). Sleep Med. 2004;5(Suppl 1):S2–8.
54. Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53(2):154–66.
55. Taheri S, Zeitzer JM, Mignot E. The role of hypocretins (orexins) in sleep regulation and narcolepsy. Annu Rev Neurosci. 2002;25:283–313.
56. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98(3):365–76.
57. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98(4):437–51.
58. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. 2001;30(2):345–54.
59. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Medicine. 2000;6(9):991–97.
60. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59(10):1553–62.
61. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469–74.
62. Hallmayer J, Faraco J, Lin L, et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genetics. 2009;41(6):708–11.
63. Kornum BR, Kawashima M, Faraco J, et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genetics. 2011;43(1):66–71.
64. Morin CM, Belanger L, LeBlanc M, et al. The natural history of insomnia: a population-based 3-year longitudinal study. Arch Intern Med. 2009;169(5):447–53.
65. Roth T, Coulouvrat C, Hajak G, et al. Prevalence and perceived health associated with insomnia based on DSM-IV-TR; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; and Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition criteria: results from the America Insomnia Survey. Biol Psychiatry. 2011;69(6):592–600.
66. Taylor DJ, Mallory LJ, Lichstein KL, et al. Comorbidity of chronic insomnia with medical problems. Sleep. 2007;30(2):213–18.
67. Ancoli-Israel S, Ayalon L, Salzman C. Sleep in the elderly: normal variations and common sleep disorders. Harv Rev Psychiatry. 2008;16(5):279–86.
68. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA. 1989;262(11):1479–84.
69. Leger D, Scheuermaier K, Philip P, et al. SF-36: evaluation of quality of life in severe and mild insomniacs compared with good sleepers. Psychosom Med. 2001;63(1):49–55.
70. Hatoum HT, Kong SX, Kania CM, et al. Insomnia, health-related quality of life and healthcare resource consumption. A study of managed-care organisation enrollees. Pharmacoeconomics. 1998;14(6):629–37.
71. Zammit GK, Weiner J, Damato N, et al. Quality of life in people with insomnia. Sleep. 1999;22(Suppl 2):S379–85.
72. Fullerton DS. The economic impact of insomnia in managed care: a clearer picture emerges. Am J Man Care. 2006;12(8 Suppl):S246–52.
73. Leger D, Massuel MA, Metlaine A. Professional correlates of insomnia. Sleep. 2006;29(2):171–78.
74. Butler AC, Chapman JE, Forman EM, et al. The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clin Psychol Rev. 2006;26(1):17–31.
75. Martin SA, Aikens JE, Chervin RD. Toward cost-effectiveness analysis in the diagnosis and treatment of insomnia. Sleep Med Rev. 2004;8(1):63–72.
76. Heath AC, Kendler KS, Eaves LJ, et al. Evidence for genetic influences on sleep disturbance and sleep pattern in twins. Sleep. 1990;13(4):318–35.
77. Heath AC, Eaves LJ, Kirk KM, et al. Effects of lifestyle, personality, symptoms of anxiety and depression, and genetic predisposition on subjective sleep disturbance and sleep pattern. Twin Res. 1998;1(4):176–88.
78. McCarren M, Goldberg J, Ramakrishnan V, et al. Insomnia in Vietnam era veteran twins: influence of genes and combat experience. Sleep. 1994;17(5):456–61.
79. Boomsma DI, van Someren EJ, Beem AL, et al. Sleep during a regular week night: a twin-sibling study. Twin Res Hum Genet. 2008;11(5):538–45.
80. Gregory AM, Rijsdijk FV, Lau JY, et al. The direction of longitudinal associations between sleep problems and depression symptoms: a study of twins aged 8 and 10 years. Sleep. 2009;32(2):189–99.
81. Watson NF, Goldberg J, Arguelles L, et al. Genetic and environmental influences on insomnia, daytime sleepiness, and obesity in twins. Sleep. 2006;29(5):645–49.
82. Viola AU, Archer SN, James LM, et al. PER3 polymorphism predicts sleep structure and waking performance. Curr Biol. 2007;17(7):613–18.
83. Laposky A, Easton A, Dugovic C, et al. Deletion of the mammalian circadian clock gene BMAL1/Mop3 alters baseline sleep architecture and the response to sleep deprivation. Sleep. 2005;28(4):395–409.
84. McClung CA. Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther. 2007;114(2):222–32.
85. Serretti A, Benedetti F, Mandelli L, et al. Genetic dissection of psychopathological symptoms: insomnia in mood disorders and CLOCK gene polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2003;121B(1):35–38.
86. Serretti A, Cusin C, Benedetti F, et al. Insomnia improvement during antidepressant treatment and CLOCK gene polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2005;137B(1):36–39.
87. Utge SJ, Soronen P, Loukola A, et al. Systematic analysis of circadian genes in a population-based sample reveals association of TIMELESS with depression and sleep disturbance. PLoS One. 2010;5(2):e9259.
88. Pack AI. Obstructive sleep apnea. Adv Intern Med. 1994;39:517–67.
89. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230–35.
90. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl Jo Med. 1999;340(11):847–51.
91. Marshall NS, Wong KK, Liu PY, et al. Sleep apnea as an independent risk factor for all-cause mortality: the Busselton Health Study. Sleep. 2008;31(8):1079–85.
92. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034–41.
93. Strohl KP, Redline S. Recognition of obstructive sleep apnea. Am J Respir Crit Care Med. 1996;154(2 Pt 1):279–89.
94. Davies RJ, Stradling JR. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J. 1990;3(5):509–14.
95. Davies RJ, Ali NJ, Stradling JR. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome. Thorax. 1992;47(2):101–05.
96. Guilleminault C, Quera-Salva MA, Partinen M, et al. Women and the obstructive sleep apnea syndrome. Chest. 1988;93(1):104–09.
97. Mathur R, Douglas NJ. Family studies in patients with the sleep apnea–hypopnea syndrome. Ann Intern Med. 1995;122(3):174–78.
98. Wetter DW, Young TB, Bidwell TR, et al. Smoking as a risk factor for sleep-disordered breathing. Arch Intern Med. 1994;154(19):2219–24.
99. Lavie P, Fischel N, Zomer J, et al. The effects of partial and complete mechanical occlusion of the nasal passages on sleep structure and breathing in sleep. Acta Otolaryngol. 1983;95(1–2):161–66.
100. Ali NJ, Pitson DJ, Stradling JR. Snoring, sleep disturbance, and behaviour in 4–5 year olds. Arch Dis Child. 1993;68(3):360–66.
101. Arens R, McDonough JM, Costarino AT, et al. Magnetic resonance imaging of the upper airway structure of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2001;164(4):698–703.
102. Guilleminault C, Li K, Quo S, et al. A prospective study on the surgical outcomes of children with sleep-disordered breathing. Sleep. 2004;27(1):95–100.
103. Strohl KP, Saunders NA, Feldman NT, et al. Obstructive sleep apnea in family members. N Engl J Med. 1978;299(18):969–73.
104. Ovchinsky A, Rao M, Lotwin I, et al. The familial aggregation of pediatric obstructive sleep apnea syndrome. Arch Otolaryngol Head Neck Surg. 2002;128(7):815–18.
105. Palmer LJ, Buxbaum SG, Larkin E, et al. A whole-genome scan for obstructive sleep apnea and obesity. Am J Hum Genetics. 2003;72(2):340–50.
106. Larkin EK, Patel SR, Elston RC, et al. Using linkage analysis to identify quantitative trait loci for sleep apnea in relationship to body mass index. Ann Hum Genet. 2008;72(Pt 6):762–73.
107. Palmer LJ, Buxbaum SG, Larkin EK, et al. Whole genome scan for obstructive sleep apnea and obesity in African-American families. Am J Respir Crit Care Med. 2004;169(12):1314–21.
108. Relf BL, Larkin EK, De Torres C, et al. Genome-wide linkage of obstructive sleep apnoea and high-density lipoprotein cholesterol in a Filipino family: bivariate linkage analysis of obstructive sleep apnoea. J Sleep Res. 2010;19(2):349–57.
109. Riha RL. Genetic aspects of the obstructive sleep apnoea/hypopnoea syndrome – is there a common link with obesity? Respiration. 2009;78(1):5–17.
110. Gottlieb DJ, Redline S, Nieto FJ, et al. Association of usual sleep duration with hypertension: the Sleep Heart Health Study. Sleep. 2006;29(8):1009–14.
111. Miyagawa T, Kawashima M, Nishida N, et al. Variant between CPT1B and CHKB associated with susceptibility to narcolepsy. Nat Genetics. 2008;40(11):1324–28.
112. Hor H, Kutalik Z, Dauvilliers Y, et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genetics. 2010;42(9):786–89.
113. Patel SR, Goodloe R, De G, et al. Association of genetic loci with sleep apnea in European Americans and African-Americans: The Candidate Gene Association Resource (CARe). PLoS One. 2012;7(11):e48836.
114. Frayling TM. Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genetics. 2007;8(9):657–62.